Safety and efficacy of upfront triple therapy including parenteral treprostinil compared to double oral therapy in PAH (TripleTRE): study protocol for a randomised trial.

Background: Pulmonary arterial hypertension (PAH) requires a complex and multidisciplinary care approach with regular follow-up visits to monitor disease progression and adaptation of treatment regimens. Current ESC/ERS Guidelines recommend initial double oral treatment (endothelin-receptor antagonist + phosphodiesterase type 5 inhibitor) in patients presenting at diagnosis with intermediate risk according to the three-strata risk score. Retrospective data analyses indicate a clinical benefit for upfront triple combination therapy including parenteral prostacyclins (PCA) in intermediate and high-risk patients. The multicentric TripleTRE trial aims to investigate the effect of initial triple combination therapy including parenteral PCA on risk status, compared to double oral in a prospective setting in patients at intermediate-high risk at diagnosis according to the four-strata risk score. Methods: A phase IV, multicentre, prospective, randomised, two-arm, open-label trial will be conducted. The study will enrol a total of 110 patients with intermediate-high risk of death at PAH diagnosis. Patients are randomised (1:1) to receive either initial double-oral treatment or upfront triple combination treatment including parenteral treprostinil. The primary end-point is the achievement of a low-risk status between week 24 and 48 assessed with the simplified four-strata risk assessment tool. Discussion: Despite retrospective evidence for greater benefit, prospective investigation of upfront triple therapy including a parenteral PCA is lacking. The TripleTRE trial aims to fill this gap and test the hypothesis of "hit hard and early" in patients with newly diagnosed PAH.